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Folding Upon Binding: Unique Protein Activation Mechanism Found by Scientists at The Scripps Research Institute

La Jolla, CA. January 31, 2002 -- A group of scientists at The Scripps Research Institute (TSRI) have solved the structure of two critical human proteins that are normally unstructured in the cell, but fold synergistically so that together they form an active biological structure.

The structures themselves may one day lead to new therapies, since the proteins are important regulators of genes essential for development and reproduction and are implicated in cancer and other diseases. Furthermore, the work provides biologists with a first glimpse of a synergistic folding mechanism-- which may be a commonplace occurrence in the cell.

The two proteins are a nuclear receptor coactivator and the general transcription coactivator called CBP, and their structure is reported in the current issue of the journal Nature by a group led by Peter E. Wright, Ph.D., who is Professor and Chairman of the Department of Molecular Biology and Cecil H. and Ida M. Green Investigator in Medical Research at TSRI.

"This [synergistic folding] is something that has never been seen before," says Wright. "We have always thought about proteins in terms of their shape, their 3-D fold. It was always assumed that the structures of proteins are responsible for their biological functions."

"We can no longer just equate structure with function," he says.

If cells are the tiny factories of life, proteins are the workers, machines, bricks, and mortar of those factories. For years biologists have solved the structures of proteins as a way of elucidating their mechanisms and understanding life on the molecular scale.

But it is now recognized that many of the proteins in the human genome are normally unstructured in the cell. By some estimates, 30 to 40 percent of the human genome codes for proteins that have either large unstructured regions or are entirely unstructured and yet are biologically functional, and there is growing evidence that much of biology is carried out by these "intrinsically unstructured proteins."

The structure, solved by Wright and his colleagues through nuclear magnetic resonance spectroscopy, demonstrates that these two intrinsically unstructured transcriptional proteins fold synergistically and become active when brought together, suggesting a novel mechanism by which this type of protein may carry out biological functions.

The structures of the proteins are also interesting from the point of view of basic biological research because they are important players in the nuclear hormone response. As critical regulators of the nuclear hormone response, these proteins provide a potential target for therapeutic intervention, specifically in certain forms of breast and cervical cancers.

The nuclear hormone response regulates the expression of genes that are essential for everything from tissue growth and development to sexual reproduction. Such important genes must be tightly regulated, and the body accomplishes this by employing transcription factors.

Transcription factors are the proteins that bind to the DNA of the genes and regulate their expression by recruiting the polymerase molecule-- cellular machine that transcribes DNA into RNA. The cell cannot initiate transcription until the polymerase is recruited by these factors.

In the nuclear hormone response, one of the important participants is the protein p160, which associates with the CBP/p300 protein. Synergistically folded CBP/p300 and p160 are "coactivators" of transcription because they make the DNA available for transcription as well as recruit the polymerase molecule.

The research article "Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators" is authored by Stephen J. Demarest, Maria Martinez-Yamout, John Chung, Hongwu Chen, Wei Xu, H. Jane Dyson, Ronald M. Evans, and Peter E. Wright and appears in the January 31, 2002 issue of Nature.

The research was funded by the National Institutes of Health and The Skaggs Institute for Research.

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